Novel, water soluble dihydropyridine compounds and their derivatives can open potassium channels and are useful for treating a variety of medical conditions.
Potassium channels play an important role in regulating cell membrane excitability. When the potassium channels open, changes in the electrical potential across the cell membrane occur and result in a more polarized state. A number of diseases or conditions can be treated with therapeutic agents that open potassium channels. See K. Lawson, Pharmacol. Ther., v. 70, pp. 39-63 (1996); D. R. Gehlert et al., Prog. NeuroPsychopharmacol and Biol. Psychiat., v. 18, pp. 1093-1102 (1994); M. Gopalakrishnan et al., Drug Development Research, v. 28, pp. 95-127 (1993); J. E. Freedman et al., The Neuroscientist, v. 2, pp. 145-152 (1996). Such diseases or conditions include asthma, epilepsy, hypertension, impotence, migraine, pain, urinary incontinence, stroke, Raynaud""s Syndrome, eating disorders, functional bowel disorders, and neurodegeneration.
Potassium channel openers also act as smooth muscle relaxants. Because urinary incontinence can result from the spontaneous, uncontrolled contractions of the smooth muscle of the bladder, the ability of potassium channel openers to hyperpolarize bladder cells and relax bladder smooth muscle provides a method to ameliorate or prevent urinary incontinence.
DE 2003148 discloses acridinedione and quinolone compounds claimed to possess spasmolytic action on the smooth muscle of the gastrointestinal tract, the urogenital tract and the respiratory system. Compunds disclosed in DE 2003148 are also claimed to have antihypertensive properties. These compounds belong to the larger general chemical class of dihydropyridines. The examples described in DE 2003148 all possess a cyclohexanone ring fused to the dihydropyridine nucleus and as a result have the disadvantage of possessing very low water solubility. This low solubility limits the utility of these agents as pharmaceuticals. Low water solubility can result in erratic patterns of absorption when drugs are administered orally. This can result in wide variability in drug absorption from patient to patient and potentially to toxic side-effects. The compounds of the present invention are chemically distinct from the examples described in DE 2003148 since they must have a cyclopentanone ring fused to the dihydropyridine ring, a structural feature that confers upon the compounds of the present invention the surprising and unexpected property of vastly superior water solubility, on average 55 times higher solubility in water than comparable analogs from DE 2003148.
WO 9408966, EP 0539153 A1 and EP 0539154 A1 disclose acridinedione and quinolone compounds that are claimed useful in the treatment of urinary incontinence. These compounds belong to the larger general chemical class of dihydropyridines. The examples described in WO 9408966, EP 0539153 A1 and EP 0539154 A1 all possess a cyclohexanone ring fused to the dihydropyridine nucleus and as a result have the disadvantage of possessing very low water solubility. This low solubility limits the utility of these agents as pharmaceuticals. Low water solubility can result in erratic patterns of absorption when drugs are administered orally. This can result in wide variability in drug absorption from patient to patient and potentially to toxic side-effects. The compounds of the present invention are chemically distinct from those of WO94/08966, EP 0539153 A1 and EP 0539154 A1 since they must have a cyclopentanone ring fused to the dihydropyridine ring, a structural feature that confers upon the compounds of the present invention the surprising and unexpected property of vastly superior water solubility, on average 55 times higher solubility in water than comparable analogs from the above inventions.
Dihydropyridines of differing chemical structure may possess a variety of biological activities. Dimmock et al (Eur. J. Med. Chem. 1988, 23, 111-117) describe a N-methyldihydropyridine containing two cyclopentanone rings fused to the dihydropyridine nucleus. The only biological activity indicated was that it was inactive against murine P388 lymphocytic leukemia. The compounds of the present invention are distinct from this compound since they must be unsubstituted at the dihydropyridine nitrogen.
EP 622366 A1 describes dihydropyridines substituted with quinolines as cardiovascular agents.
EP 299727 describes 4-aryl-(5,6-bicyclo)-2-(imidazol-1-ylalkoxymethyl)dihydropyridines as platelet activating factor (PAF) antagonists.
WO 9012015-A describes dihydropyridines that are claimed to be PAF antagonists. EP 173943-A describes dihydropyridines that are modifiers of enzymes involved in arachidonic acid metabolism. EP 186027-A describes dihydropyridines that have vasodilating properties. All of these patents describe dihydropyridines that generically claim a cyclopentanone fused on one side of the dihydropyridine with carboxylic esters on the other side.
Thus, the compounds of the present invention are chemically distinct from the prior art, are water soluble, hyperpolarize cell membranes, open potassium channels, relax smooth muscle cells, inhibit bladder contractions and are useful for treating diseases that can be ameliorated by opening potassium channels.
In its principle embodiment, the present invention discloses compounds having formula I: 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein, a broken line represents the presence of an optional double bond;
R1 is selected from the group consisting of aryl and heteroaryl;
A is selected from the group consisting of hydrogen, alkyl, cyano, haloalkyl, heteroaryl, nitro, and xe2x80x94C(O)R2, wherein, R2 is selected from the group consisting of alkyl, haloalkyl, and hydroxy;
R3 is selected from the group consisting of hydrogen, alkyl, and haloalkyl; and
A and R3 taken together with the ring to which they are attached can form a 5- or 6-membered carbocyclic ring, said 5- or 6-membered carbocyclic ring can contain 1 or 2 double bonds, and can be substituted with 1 or 2 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, arylalkoxy, haloalkenyl, haloalkyl, halogen, hydroxy, hydroxyalkenyl, hydroxyalkyl, oxo, and xe2x80x94NR4R5 wherein, R4 and R5 are independently selected from the group consisting of hydrogen and lower alkyl.
Another embodiment of the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof in combination with a pharmaceutically acceptable carrier.
Yet another embodiment of the invention relates to a method of treating asthma, epilepsy, hypertension, Raynaud""s syndrome, impotence, migraine, pain, eating disorders, urinary incontinence, functional bowel disorders, neurodegeneration and stroke comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
In one embodiment, compounds of the present invention have formula I: 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein, a broken line represents the presence of an optional double bond;
R1 is selected from the group consisting of aryl and heteroaryl;
A is selected from the group consisting of hydrogen, alkyl, cyano, haloalkyl, heteroaryl, nitro, and xe2x80x94C(O)R2, wherein, R2 is selected from the group consisting of alkyl, haloalkyl, and hydroxy;
R3 is selected from the group consisting of hydrogen, alkyl, and haloalkyl; and
A and R3 taken together with the ring to which they are attached can form a 5- or 6-membered carbocyclic ring, said 5- or 6-membered carbocyclic ring can contain 1 or 2 double bonds, and can be substituted with 1 or 2 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, arylalkoxy, haloalkenyl, haloalkyl, halogen, hydroxy, hydroxyalkyl, hydroxyalkenyl, oxo, and xe2x80x94NR4R5 wherein, R4 and R5 are independently selected from the group consisting of hydrogen and lower alkyl.
In another embodiment of the present invention, compounds have formula I wherein, A is selected from the group consisting of hydrogen, alkyl, cyano, nitro, and haloalkyl; and R3 is hydrogen.
In another embodiment of the present invention, compounds have formula I wherein, A is selected from the group consisting of hydrogen, alkyl, cyano, nitro, and haloalkyl; and R3 is selected from the group consisting of alkyl.
In another embodiment of the present invention, compounds have formula I wherein, A is selected from the group consisting of hydrogen, alkyl, cyano, nitro, and haloalkyl; and R3 is selected from the group consisting of haloalkyl.
In another embodiment of the present invention, compounds have formula I wherein, A is xe2x80x94C(O)R2 wherein R2 is selected from the group consisting of alkyl, haloalkyl, and hydroxy; and R3 is hydrogen.
In another embodiment of the present invention, compounds have formula I wherein, A is xe2x80x94C(O)R2 wherein R2 is selected from the group consisting of alkyl, haloalkyl, and hydroxy; and R3 is selected from the group consisting of alkyl.
In another embodiment of the present invention, compounds have formula I wherein, A is xe2x80x94C(O)R2 wherein R2 is selected from the group consisting of alkyl, haloalkyl, and hydroxy; and R3 is selected from the group consisting of haloalkyl.
In another embodiment of the present invention, compounds have formula I wherein, A is xe2x80x94C(O)R2 wherein R2 is hydroxy; and R3 is selected from the group consisting of alkyl wherein lower alkyl is preferred.
In another embodiment of the present invention, compounds have formula I wherein, A is heteroaryl; and R3 is selected from the group consisting of hydrogen, alkyl, and haloalkyl.
In another embodiment of the present invention, compounds have formula I wherein, A is tetrazole; and R3 is selected from the group consisting of hydrogen, alkyl, and haloalkyl.
In a preferred embodiment, compounds of the present invention have formula II: 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein, a broken line represents the presence of an optional double bond; m is an integer 1-2; R1 is selected from the group consisting of aryl and heteroaryl; D and Dxe2x80x2 are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, arylalkoxy, haloalkenyl, haloalkyl, halogen, hydroxy, hydroxyalkenyl, hydroxyalkyl, oxo, and xe2x80x94NR4R5 wherein, R4 and R5 are independently selected from the group consisting of hydrogen and lower alkyl.
In another preferred embodiment, compounds of the present invention have formula III: 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein, m is an integer 1-2; R1 is selected from the group consisting of aryl and heteroaryl; D and Dxe2x80x2 are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, arylalkoxy, haloalkenyl, haloalkyl, halogen, hydroxy, hydroxyalkenyl, hydroxyalkyl, oxo, and xe2x80x94NR4R5 wherein, R4 and R5 are independently selected from the group consisting of hydrogen and lower alkyl.
In another preferred another embodiment, compounds of the present invention have formula IV: 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein, m is an integer 1-2; R1 is selected from the group consisting of aryl and heteroaryl; D and Dxe2x80x2 are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, arylalkoxy, haloalkenyl, haloalkyl, halogen, hydroxy, hydroxyalkenyl, hydroxyalkyl, oxo, and xe2x80x94NR4R5 wherein, R4 and R5 are independently selected from the group consisting of hydrogen and lower alkyl.
In another preferred embodiment, compounds of the present invention have formula V: 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein m is an integer 1-2; R1 is selected from the group consisting of aryl and heteroaryl; D and Dxe2x80x2 are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, arylalkoxy, haloalkenyl, haloalkyl, halogen, hydroxy, hydroxyalkenyl, hydroxyalkyl, oxo, and xe2x80x94NR4R5 wherein, R4 and R5 are independently selected from the group consisting of hydrogen and lower alkyl.
In a more preferred embodiment of the present invention, compounds have formula V, wherein, m is 1; D is hydrogen; Dxe2x80x2 is hydrogen; and R1 is aryl wherein, a preferred aryl is phenyl substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, aryl, azido, arylalkyl, aryloxy, carboxy, cyano, formyl, halogen, haloalkyl, haloalkyloxy, heteroaryl, hydroxy, methylenedioxy, mercapto, nitro, sulfamyl, sulfo, sulfonate, thioureylene, ureylene, and xe2x80x94C(O)NR80R81 wherein, R80 and R81 are independently selected from hydrogen, alkyl, aryl and arylalkyl. Most preferred phenyl substituents are selected from cyano, halogen and nitro.
In another more preferred embodiment of the present invention, compounds have formula V wherein, m is 1; D is hydrogen; Dxe2x80x2 is hydrogen; and R1 is heteroaryl, more preferred heteroaryls include, but are not limited to, benzoxadiazole, benzoxazole, benzothiazole, benzothiadiazole, benzothiophene, benzofuran, furan, and thiophene. A most preferred heteroaryl is 2,1,3-benzoxadiazole.
In another preferred embodiment, compounds of the present invention have formula VI: 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein, m is an integer 1-2; R1 is selected from the group consisting of aryl and heteroaryl; D and Dxe2x80x2 are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, arylalkoxy, haloalkenyl, haloalkyl, halogen, hydroxy, hydroxyalkenyl, hydroxyalkyl, oxo, and xe2x80x94NR4R5 wherein, R4 and R5 are independently selected from the group consisting of hydrogen and lower alkyl.
In another more preferred embodiment of the present invention, compounds have formula VI wherein, m is 2; D is hydrogen; Dxe2x80x2 is hydrogen; and R1 is aryl wherein, a preferred aryl is phenyl substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, aryl, azido, arylalkyl, aryloxy, carboxy, cyano, formyl, halogen, haloalkyl, haloalkyloxy, heteroaryl, hydroxy, methylenedioxy, mercapto, nitro, sulfamyl, sulfo, sulfonate, thioureylene, ureylene, and xe2x80x94C(O)NR80R81 wherein, R80 and R81 are independently selected from hydrogen, alkyl, aryl and arylalkyl. Most preferred phenyl substituents are selected from cyano, halogen and nitro.
The present invention also relates to pharmaceutical compositions which comprise a therapeutically effective amount of a compound of formulae I-VI or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof in combination with a pharmaceutically acceptable carrier.
The present invention also relates to a method of treating a disease in a mammal comprising administering an effective amount of a compound of formulae I-VI or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
In particular, the present invention relates to a method of treating asthma, epilepsy, hypertension, Raynaud""s syndrome, impotence, migraine, pain, eating disorders, urinary incontinence, functional bowel disorders, neurodegeneration and stroke comprising administering an effective amount of a compound of formulae I-VI or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
Definition of Terms
As used throughout this specification and the appended claims, the following terms have the following meanings.
The term xe2x80x9calkenyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon containing from 2-to-10 carbons and containing at least one carbonxe2x80x94carbon double bond formed by the removal of two hydrogens. Representative examples of xe2x80x9calkenylxe2x80x9d include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl and the like.
The term xe2x80x9calkoxy,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.
The term xe2x80x9calkoxyalkoxy,xe2x80x9d as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through another alkoxy group, as defined herein. Representative examples of alkoxyalkoxy include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, methoxymethoxy, and the like.
The term xe2x80x9calkoxyalkyl,xe2x80x9d as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, methoxymethyl, and the like.
The term xe2x80x9calkoxycarbonyl,xe2x80x9d as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, and the like.
The term xe2x80x9calkyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon containing from 1-to-10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.
The term xe2x80x9calkylcarbonyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, 1-oxopentyl, and the like.
The term xe2x80x9calkylcarbonyloxy,xe2x80x9d as used herein, refers to an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, tert-butylcarbonyloxy, and the like.
The term xe2x80x9calkylsulfinyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfinyl group, as defined herein. Representative examples of alkylsulfinyl include, but are not limited, methylsulfinyl, ethylsulfinyl, and the like.
The term xe2x80x9calkylsulfonyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkylsulfonyl include, but are not limited, methylsulfonyl, ethylsulfonyl, and the like.
The term xe2x80x9calkylthio,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a thio group, as defined herein. Representative examples of alkylthio include, but are not limited, methylthio, ethylthio, tert-butylthio, hexylthio, and the like.
The term xe2x80x9calkynyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon group containing from 2-to-10 carbon atoms and containing at least one carbonxe2x80x94carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 1-butynyl and the like.
The term xe2x80x9camino,xe2x80x9d as used herein, refers to xe2x80x94NH2.
The term xe2x80x9caminocarbonyl,xe2x80x9d as used herein, refers to a xe2x80x94C(O)NH2 group.
The term xe2x80x9calkylamino,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an amino group, as defined herein. Representative examples of alkylamino include, but are not limited to, methylamino, ethylamino, propylamino, tert-butylamino, and the like.
The term xe2x80x9cdialkylamino,xe2x80x9d as used herein, refers to two independent alkyl groups, as defined herein, appended to the parent molecular moiety through an amino group, as defined herein. Representative examples of dialkylamino include, but are not limited to, dimethylamino, diethylamino, ethylmethylamino, butylmethylamino, ethylhexylamino, and the like.
The term xe2x80x9caryl,xe2x80x9d as used herein, refers to a monocyclic carbocyclic ring system or a bicyclic carbocyclic fused ring system having one or more aromatic rings. Representative examples of aryl include, azulenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like.
The aryl groups of this invention can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, aryl, azido, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, formyl, halogen, haloalkyl, haloalkoxy, heteroaryl, hydroxy, methylenedioxy, mercapto, nitro, sulfamyl, sulfo, sulfonate, thioureylene, ureylene, xe2x80x94NR80R81 (wherein, R80 and R81 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl and formyl), and xe2x80x94C(O)NR82R83 (wherein, R82 and R83 are independently selected from hydrogen, alkyl, aryl, and arylalkyl.
The term xe2x80x9carylalkoxy,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of arylalkoxy include, but are not limited to, 2-phenylethoxy, 3-naphth-2-ylpropoxy, 5-phenylpentyloxy, and the like.
The term xe2x80x9carylalkoxycarbonyl,xe2x80x9d as used herein, refers to an arylalkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylalkoxy include, but are not limited to, benzyloxycarbonyl, naphth-2-ylmethoxycarbonyl, and the like.
The term xe2x80x9carylalkyl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and the like.
The term xe2x80x9caryloxy,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein.
The term xe2x80x9cazido,xe2x80x9d as used herein, refers to an xe2x80x94N3 group.
The term xe2x80x9ccarbonyl,xe2x80x9d as used herein, refers to a xe2x80x94C(O)xe2x80x94 group.
The term xe2x80x9ccarboxy,xe2x80x9d as used herein, refers to a xe2x80x94CO2H group.
The term xe2x80x9ccarboxyalkyl,xe2x80x9d as used herein, refers to a carboxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of carboxyalkyl include, but are not limited to, 2-carboxyethyl, 3-carboxypropyl, and the like.
The term xe2x80x9ccarboxy protecting group,xe2x80x9d as used herein, refers to a carboxylic acid protecting ester group employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites of the compound are carried out. Carboxy-protecting groups are disclosed in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991), which is hereby incorporated herein by reference. In addition, a carboxy-protecting group can be used as a prodrug whereby the carboxy-protecting group can be readily cleaved in vivo, for example by enzymatic hydrolysis, to release the biologically active parent. T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in xe2x80x9cPro-drugs as Novel Delivery Systemsxe2x80x9d, Vol 14 of the A.C.S. Symposium Series, American Chemical Society (1975), which is hereby incorporated herein by reference. Such carboxy-protecting groups are well known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields, as described in U.S. Pat. Nos. 3,840,556 and 3,719,667, the disclosures of which are hereby incorporated herein by reference. Examples of esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of xe2x80x9cBioreversible Carriers in Drug Design: Theory and Applicationxe2x80x9d, edited by E. B. Roche, Pergamon Press, New York (1987), which is hereby incorporated herein by reference. Representative carboxy-protecting groups are loweralkyl (e.g., methyl, ethyl or tertiary butyl and the like); benzyl (phenylmethyl) and substituted benzyl derivatives thereof such substituents are selected from alkoxy, alkyl, halogen, and nitro groups and the like.
The term xe2x80x9ccyano,xe2x80x9d as used herein, refers to a xe2x80x94CN group.
The term xe2x80x9ccyanoalkyl,xe2x80x9d as used herein, refers to a cyano group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, and the like.
The term xe2x80x9ccycloalkylxe2x80x9d, as used herein, refers to a saturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
The term xe2x80x9ccycloalkylalkyl,xe2x80x9d as used herein, refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and 4-cycloheptylbutyl, and the like.
The term xe2x80x9cethylenedioxy,xe2x80x9d as used herein, refers to a xe2x80x94O(CH2)2Oxe2x80x94 group wherein, the oxygen atoms of the ethylenedioxy group are attached to the same carbon atom or the oxygen atoms of the ethylenedioxy group are attached to two adjacent carbon atoms.
The term xe2x80x9cformyl,xe2x80x9das used herein, refers to a xe2x80x94C(O)H group.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogen,xe2x80x9d as used herein, refers to xe2x80x94Cl, xe2x80x94Br, xe2x80x94I or xe2x80x94F.
The term xe2x80x9chaloalkenyl,xe2x80x9d as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkenyl group, as defined herein. Representative examples of haloalkenyl include, but are not limited to, 4-chlorobuten-1-yl, 4,4,4-trifluorobuten-1-yl, and the like.
The term xe2x80x9chaloalkyl,xe2x80x9d as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, and the like.
The term xe2x80x9chaloalkoxy,xe2x80x9d as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of haloalkoxy include, but are not limited to, 2-chloroethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, and the like.
The term xe2x80x9cheteroaryl,xe2x80x9d as used herein, refers to a monocyclic- or a bicyclic-ring system. Monocyclic ring systems are exemplified by any 5- or 6-membered ring containing 1, 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur. The 5-membered ring has from 0-2 double bonds and the 6-membered ring has from 0-3 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine, tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole, thiazoline, thiazolidine, thiophene, thiomorpholine, thiomorpholine sulfone, thiopyran, triazine, triazole, trithiane, and the like. Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system as defined herein. Representative examples of bicyclic ring systems include but are not limited to, for example, benzimidazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxine, 1,3-benzodioxole, cinnoline, indazole, indole, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, pyranopyridine, quinoline, quinolizine, quinoxaline, quinazoline, tetrahydroisoquinoline, tetrahydroquinoline, and thiopyranopyridine.
The heteroaryl groups of this invention can be substituted with 1, 2, or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, aryl, azido, arylalkoxy, arylalkoxycarbonyl, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, ethylenedioxy, formyl, halogen, haloalkyl, haloalkoxy, heteroaryl, hydroxy, methylenedioxy, mercapto, nitro, oxo, sulfamyl, sulfo, sulfonate, thioureylene, ureylene, xe2x80x94NR80R81 (wherein, R80 and R81 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl and formyl), and xe2x80x94C(O)NR82R83 (wherein, R82 and R83 are independently selected from hydrogen, alkyl, aryl, and arylalkyl.
The term xe2x80x9chydroxy,xe2x80x9d as used herein, refers to an xe2x80x94OH group.
The term xe2x80x9chydroxyalkenyl,xe2x80x9d as used herein, refers to a hydroxy group, as defined herein, appended to the parent molecular moiety through an alkenyl group, as defined herein. Representative examples of hydroxyalkenyl include, but are not limited to, 4-hydroxybuten-1-yl, 5-hydroxypenten-1-yl, and the like.
The term xe2x80x9chydroxyalkyl,xe2x80x9d as used herein, refers to a hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-ethyl-4-hydroxyheptyl, and the like.
The term xe2x80x9clower alkoxy,xe2x80x9d as used herein, refers to a lower alkyl group, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein. Representative examples of lower alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, and the like.
The term xe2x80x9clower alkyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon group containing from 1-to-4 carbon atoms. Representative examples of lower alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, and the like.
The term xe2x80x9cmammal,xe2x80x9d as used herein, has its ordinary meaning and includes human beings.
The term xe2x80x9cmercapto,xe2x80x9d as used herein, refers to a xe2x80x94SH group.
The term xe2x80x9cmethylenedioxy,xe2x80x9d as used herein, refers to a xe2x80x94OCH2Oxe2x80x94 group wherein, the oxygen atoms of the methylenedioxy group are attached to two adjacent carbon atoms.
The term xe2x80x9cnitro,xe2x80x9d as used herein, refers to a xe2x80x94NO2 group.
The term xe2x80x9coxo,xe2x80x9d as used herein, refers to a xe2x95x90O moiety.
The term xe2x80x9coxy,xe2x80x9d as used herein, refers to a xe2x80x94Oxe2x80x94 moiety.
The term xe2x80x9csulfamyl,xe2x80x9d as used herein, refers to a xe2x80x94SO2NR94R95 group, wherein, R94 and R95 are independently selected from hydrogen, alkyl, aryl, and arylalkyl, as defined herein.
The term xe2x80x9csulfinyl,xe2x80x9d as used herein, refers to a xe2x80x94S(O)xe2x80x94 group.
The term xe2x80x9csulfo,xe2x80x9d as used herein, refers to a xe2x80x94SO3H group.
The term xe2x80x9csulfonate,xe2x80x9d as used herein, refers to a xe2x80x94S(O)2OR96 group, wherein, R96 is selected from alkyl, aryl, and arylalkyl, as defined herein.
The term xe2x80x9csulfonyl,xe2x80x9d as used herein, refers to a xe2x80x94SO2xe2x80x94 group.
The term xe2x80x9cthio,xe2x80x9d as used herein, refers to a xe2x80x94Sxe2x80x94 moiety.
The term xe2x80x9cthioureylene,xe2x80x9d as used herein, refers to xe2x80x94NR97C(S)NR98R99, wherein, R97, R98, and R99 are independently selected from hydrogen, alkyl, aryl, and arylalkyl, as defined herein.
The term xe2x80x9cureylene,xe2x80x9d as used herein, refers to xe2x80x94NR97C(O)NR98R99, wherein, R97, R98, and R99 are independently selected from hydrogen, alkyl, aryl, arylalkyl, as defined herein.
Preferred compounds of formula I include,
8-(3-Bromo-4-fluorophenyl)-2,3,4,5,6,8-hexahydrodicyclopenta[b,e]pyridine-1,7-dione,
8-(3-Cyanophenyl)-2,3,4,5,6,8-hexahydrodicyclopenta[b,e]pyridine-1,7-dione,
8-(4-Chloro-3-nitrophenyl)-2,3,4,5,6,8-hexahydrodicyclopenta[b,e]pyridine-1,7-dione,
8-(3-Nitrophenyl)-2,3,4,5,6,8-hexahydrodicyclopenta[b,e]pyridine-1,7-dione,
8-(3-Chloro-4-fluorophenyl)-2,3,4,5,6,8-hexahydrodicyclopenta[b,e]pyridine-1,7-dione,
8-(3,4-Dichlorophenyl)-2,3,4,5,6,8-hexahydrodicyclopenta[b,e]pyridine-1,7-dione,
8-(2,1,3-benzoxadiazol-5-yl)-2,3,4,5,6,8-hexahydrodicyclopenta[b,e]pyridine-1,7-dione, and
8-(3-Iodo-4-fluorophenyl)-2,3,4,5,6,8-hexahydrodicyclopenta[b,e]pyridine-1,7-dione, and
9-(3-bromo-4-fluorophenyl)-5,6,7,9-tetrahydro-1H-cyclopenta[b]quinoline-1,8(4H)-dione,
4-(3-bromo-4-fluorophenyl)-2-methyl-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylic acid, and pharmaceutically acceptable salts, esters, amides, or prodrugs thereof.
The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes and methods which illustrate a means by which the compounds of the invention can be prepared.
The compounds of this invention can be prepared by a variety of synthetic routes. Representative procedures are shown in Schemes 1-9. For Schemes 1-9, R1 is selected from aryl and heteroaryl; A is selected from hydrogen, alkyl, cyano, haloalkyl, heteroaryl, nitro, and xe2x80x94C(O)R2 wherein R2 is selected from alkyl, haloalkyl, and hydroxy; R3 is selected from hydrogen, alkyl, and haloalkyl; A and R3 taken together with the carbon atoms to which they are attached can form a 5 or 6 membered carbocyclic ring which can contain 1 or 2 double bonds, and can be substituted with 1 or 2 substituents selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, arylalkoxy, haloalkenyl, haloalkyl, halogen, hydroxy, hydroxyalkenyl, hydroxyalkyl, oxo, and xe2x80x94NR4R5 wherein R4 and R5 are independently selected hydrogen and lower alkyl; and a broken line can represent an optional double bond. 
As shown in Scheme 1, the dihydropyridines of formula (vii), wherein R1, R3, and A, are as defined in formula I, can be prepared by one of three general methods. According to Path A, 1,3-cyclopentanedione (i) may be reacted with an aldehyde (ii) and an appropriate enamine component (iii) with heating in a protic solvent such as ethanol, methanol, isopropanol etc. or in dimethylformamide (DMF), or acetonitrile. A subsequent period of heating may be required with an acid such as hydrochloric acid, sulfuric acid or toluenesulfonic acid in order to drive the reaction to completion. According to Path B, 3-amino-2-cyclopenten-1-one (iv) may be reacted with an aldehyde (ii) and an appropriate carbonyl component (v) using the same reaction conditions as for Path A. According to Path C, 1,3-cyclopentanedione (i) together with an ammonia source such as ammonia in ethanol, ammonium acetate, or ammonium hydroxide, may be reacted using the same conditions as for Path A with an enone (vi) component that has been prepared from an aldehyde (ii) and a carbonyl component (v). Alternatively in Path C, 3-amino-2-cyclopenten-1-one (iv) may be substituted for the 1,3-cyclopentanedione (i) and the ammonia source using the same reaction conditions described for Path A. 
As shown in Scheme 2, dihydropyridines of formula (viii), wherein R1 is defined as in formula I, may be prepared by reacting 2 equivalents of 1,3-cyclopentanedione (i) with an aldehyde (ii) and an ammonia source such as ammonia in ethanol, ammonium acetate or ammonium hydroxide with heating in a protic solvent such as ethanol, methanol, isopropanol etc. or in dimethylformamide (DMF), or acetonitrile. A subsequent period of heating may be required with an acid such as hydrochloric acid, sulfuric acid or toluenesulfonic acid in order to drive the reaction to completion. Alternatively, 1,3-cyclopentanedione (i) may be reacted with an aldehyde (ii) and 3-amino-2-cyclopenten-1-one (iv) heating in the same solvents as above. A subsequent period of heating may be required with an acid such as hydrochloric acid or toluenesulfonic acid in order to drive the reaction to completion. 
As shown in Scheme 3, the dihydropyridines of formula (x), wherein R1, R3, and A, are as defined in formula I, can be prepared by one of two general methods. According to Path A, 1,3-cyclopentenedione (ix) may be reacted with an aldehyde (ii) and an appropriate carbonyl component (v) together with an ammonia source such as ammonia in ethanol, ammonium acetate, or ammonium hydroxide, with heating in a protic solvent such as ethanol, methanol, isopropanol etc. or in dimethylformamide (DMF), or acetonitrile. A subsequent period of heating may be required with an acid such as hydrochloric acid, sulfuric acid or toluenesulfonic acid in order to drive the reaction to completion. Alternatively, an appropriate enamine (iii) may be substituted for the carbonyl component (v) and ammonia source using the same reaction conditions. According to Path B, 1,3-cyclopentenedione (ix) together with an ammonia source such as ammonia in ethanol, ammonium acetate, or ammonium hydroxide, may be reacted using the same conditions as for Path A with an enone (vi) component that has been prepared from an aldehyde (ii) and a carbonyl component(v). 
As shown in Scheme 4, dihydropyridines of general formula (xii), wherein R1 is defined in formula I, may be prepared by reacting 1,3-cyclopentenedione (ix) with an aldehyde (ii) and 3-amino-2-cyclohexen-1-one (xi) with heating in a protic solvent such as ethanol, methanol, isopropanol etc. or in dimethylformamide (DMF), or acetonitrile. 
As shown in Scheme 5, the dihydropyridines of formula (xvii), wherein R1 and A are as defined in formula I, can be prepared by one of two general methods. According to Path A, 1,3-cyclopentanedione or 1,3-cyclopentenedione, described by (xiii), together with an ammonia source such as ammonia in ethanol, ammonium acetate, or ammonium hydroxide, may be heated in a protic solvent such as ethanol, methanol, isopropanol etc. or in dimethylformamide (DMF), or acetonitrile with an enone (xiv) component that has been prepared from an aldehyde (ii) and a carbonyl component (xv). An intermediate hemiaminal (xvi) or the desired dihydropyridine(xvii) may be isolated. In the case where the hemiaminal (xvi) is isolated, this may be converted to the dihydropyridine (xvii) by heating with an acid such as hydrochloric acid, sulfuric acid or toluenesulfonic acid under an inert atmosphere such as nitrogen or argon in order to drive the reaction to completion. This dehydration reaction may also be accomplished with POCl3 in pyridine. Alternatively, 3-amino-2-cyclopenten-1-one (iv) may be substituted for 1,3-cyclopentanedione (xiii) wherein the double bond is absent, and ammonia in Path A. According to Path B, 1,3-cyclopentanedione or 1,3-cyclopentenedione (xiii) together with an ammonia source such as ammonia in ethanol, ammonium acetate, or ammonium hydroxide, may be heated in a protic solvent such as ethanol, methanol, isopropanol etc. or in dimethylformamide (DMF), or acetonitrile with a carbonyl component (xv). Any hemiaminal (xvi) intermediate obtained via this route may be converted to the dihydropyridine (xvii) as above. 
As shown in Scheme 6, the dihydropyridines of formula (xxi), wherein R1 and R3 are as defined in formula I and R is selected from alkyl, arylalkyl, cyanoalkyl, and a carboxy protecting group, can be prepared by one of three general methods. According to Path A, 1,3-cyclopentanedione or 1,3-cyclopentenedione (xiii) may be reacted with an aldehyde (ii) and an appropriate enamine component (xviii) with heating in a protic solvent such as ethanol, methanol, isopropanol etc. or in dimethylformamide (DMF), or acetonitrile. A subsequent period of heating may be required with an acid such as hydrochloric acid, sulfuric acid or toluenesulfonic acid in order to drive the reaction to completion. According to Path B, 3-amino-2-cyclopenten-1-one (iv) may be reacted with an aldehyde (ii) and an appropriate carbonyl component (xix) using the same reaction conditions as for Path A. According to Path C, 1,3-cyclopentanedione or 1-3-cyclopentenedione (xiii) together with an ammonia source such as ammonia in ethanol, ammonium acetate, or ammonium hydroxide, may be reacted using the same conditions as for Path A with an enone component (xx) that has been prepared from an aldehyde (ii) and a carbonyl component (xix). Alternatively in Path C, 3-amino-2-cyclopenten-1-one (iv) may be substituted for the 1,3-cyclopentanedione (xiii) wherein the double bond is absent, and the ammonia source using the same reaction conditions. 
In Scheme 7, dihydropyridines (xxiii) can be prepared from the carboxylic esters (xxi), wherein R1 and R3 are as defined in formula I and R is selected from alkyl, arylalkyl, cyanoalkyl, and a carboxy protecting group. The esters may be cleaved to the carboxylic acids (xxii) using a variety of conditions dependent upon the nature of the group R. In cases where R is an alkyl group this process may be best accomplished with boron trichloride (BCl3) in a solvent such as dichloromethane or chloroform. For cases where R is cyanoethyl, this cleavage is accomplished by treatment with base such as potassium carbonate in a solvent such as. Other types of esters may be removed by methods well-known to those skilled in the art such as acid treatment or hydrogenolysis. The carboxylic acid group of (xxii) may also be removed by decarboxylation to give dihydropyridines (xxiii). Typical conditions include heating in a solvent such as ethanol or toluene in the absence or the presence of an acid such as hydrochloric acid, sulfuric acid or toluenesulfonic acid under an inert atmosphere such as nitrogen or argon. 
As shown in Scheme 8, the hemiaminals of formula (xxv), wherein R1 is defined in formula I and R is selected from alkyl, arylalkyl, cyanoalkyl, and a carboxy protecting group, can be prepared by one of two general methods. According to Path A, 1,3-cyclopentanedione or 1,3-cyclopentenedione (xiii) and an aldehyde (ii) together with an ammonia source such as ammonia in ethanol, ammonium acetate, or ammonium hydroxide, may be heated in a protic solvent such as ethanol, methanol, isopropanol etc. or in dimethylformamide (DMF), or acetonitrile with a xcex2-ketoester component (xxiv). According to Path B, 3-amino-2-cyclopenten-1-one (iv) may be substituted for the 1,3-cyclopentanedione (xiii) wherein a double bond is absent, and ammonia source of Path A. An intermediate hemiaminal (xxv) or the desired dihydropyridine (xxvi) may be isolated. In the case where the hemiaminal (xxv) is isolated, this may be converted to the dihydropyridine (xxvi) by heating with an acid such as hydrochloric acid, sulfuric acid or toluenesulfonic acid acid under an inert atmosphere such as nitrogen or argon in order to drive the reaction to completion. This dehydration reaction may also be accomplished with POCl3 in pyridine. The carboxylic esters (xxvi) may be cleaved to the carboxylic acids (xxvii) using a variety of conditions dependent upon the nature of the group R. In cases where R is an alkyl group this process may be best accomplished with boron trichloride (BCl3) in a solvent such as dichloromethane or chloroform. For cases where R is cyanoethyl, this cleavage is accomplished by treatment with base such as potassium carbonate in a solvent. Other types of esters may be removed by methods well-known to those skilled in the art such as acid treatment or hydrogenolysis. The carboxylic acid (xxvii) group may also be removed by decarboxylation to give dihydropyridines (xxviii). Typical conditions include heating in a solvent such as ethanol or toluene in the absence or the presence of an acid such as hydrochloric acid, sulfuric acid or toluenesulfonic acid under an inert atmosphere such as nitrogen or argon. 
As shown in Scheme 9, wherein R1 and R3 are as defined in formula I, Examples of the present invention that possess a center of chirality and thus exist in racemic form may be separated into the individual enantiomers by the method shown in Scheme 9. The racemic carboxylic acid (xxi) may be converted to an intermediate acid chloride using thionylchloride, oxalylchloride or similar reagent. The acid chloride is generally not isolated but treated directly with (R) or (S) mandelic aicd to produce a mixture of diastereomeric mandelic acid esters (xxiv) and (xxx). These diastereomeric esters (xxiv) and (xxx) may be separated using column chromatography on silica gel. The individually separated mandelic acid esters (xxiv) and (xxx) may be cleaved to the enantiomerically pure carboxylic acids (xxxiii) and (xxxi) respectively, by treatment with BCl3 in a solvent such as dichloromethane or chloroform. Alternatively, the mandelic acid esters (xxiv) and (xxx) may be first converted to the corresponding methyl esters by treatment with sodium methoxide in methanol prior to cleavage to the carboxylic acid as described above. Alternative methods for separating the carboxylic acids (xxiv) and (xxx) into the single enantiomers include reaction of the racemic carboxylic acid (xxi) with xcex1-methylbenzylamine or phenylglycinol and separation of the diastereomeric salts by crystallization. The carboxylic acid group of the single enantiomers (xxxiii) and (xxxi) may also be removed by decarboxylation to give chiral dihydropyridines (xxxiv) and (xxxii) respectively. Typical conditions include heating in a solvent such as ethanol or toluene in the absence or the presence of an acid such as hydrochloric acid, sulfuric acid or toluenesulfonic acid under an inert atmosphere such as nitrogen or argon. Racemic compounds of the present invention may also be separated into the individual enantiomers by chiral chromatography.
Abbreviations
The following abbreviations are used: K2CO3 for potassium carbonate, LiAlH4 for lithium aluminum hydride, AlH3 for aluminum hydrate, BH3 for borane, BH3.DMS for borane dimethylsulfide complex, DMF for dimethylformamide, DMSO for dimethylsulfoxide, Et3N for triethylamine, Et2O for diethyl ether, EtOAc for ethyl acetate, EtOH for ethanol, KOtBu for potassium tert-butoxide, LDA for lithium diisopropylamide, MeOH for methanol, NaOMe for sodium methoxide, NaOH for sodium hydroxide, HCl for hydrochloric acid, H2/Pd for hydrogen and a palladium catalyst, iPrOH for isopropyl alcohol and THF for tetrahydrofuran, cat. TFA for catalytic trifluoroacetic acid, TFA for catalytic trifluoroacetic acid, PPh3/CCl4 for triphenyl phosphine/carbon tetrachloride, and n-BuLi for n-butyllithium.
The compounds and processes of the present invention will be better understood by reference to the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention. Further, all citations herein are incorporated by reference.